1gqs

ACETYLCHOLINESTERASE (E.C. 3.1.1.7) COMPLEXED WITH NAP
(see also AChE inhibitors and substrates (Part III))



Rivastigmine (Exelon) is a carbamate inhibitor of AChE, and it is currenly used in therapy of Alzheimer's disease. Here is the active-site gorge of the rivastigmine/TcAChE complex. The carbamyl moiety of rivastigmine is covalently bound to the active-site S200 Oγ. The leaving group of rivastigmine, ((−)-S-3-[1-(dimethylamino)ethyl]phenol) (NAP) is also seen in the active-site gorge, but it is separated from the carbamyl moiety, hence, carbamylation took place. The crystal structure of NAP/TcAChE NAP (colored magenta) (without the carbamyl moiety) was determined (present entry - 1gqs). The TcAChE active-site residues interacting with NAP are colored violet. NAP is located in relatively similar region of the TcAChE active site, but with different orientation to that of the NAP moiety of rivastigmine. Only H440 and F330 significantly change their side-chain conformations. Overlap of the TcAChE active sites in 4 different complexes (with rivastigmine (1gqr), NAP (1gqs), ACh (2ace), and the additional AChE inhibitor VX (1vxr)) revealed that the conformation of H440 in the NAP/TcAChE is similar to that of native TcAChE (2ace), but the distance between H440 Nδ and E327 Oε is significantly longer in the rivastigmine/TcAChE and the VX/TcAChE complexes. This structural change disrupts the catalytic triad consisting of E327, H440, and S200. This could explain the very slow kinetics of AChE reactivation after its inhibition by rivastigmine.

About this Structure
1GQS is a Single protein structure of sequence from Torpedo californica. Full crystallographic information is available from OCA.

Additional Resources
For additional information, see: Alzheimer's Disease

Reference
Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine., Bar-On P, Millard CB, Harel M, Dvir H, Enz A, Sussman JL, Silman I, Biochemistry. 2002 Mar 19;41(11):3555-64. PMID:11888271

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